• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

CRL5-SPSB3 泛素连接酶将核 cGAS 靶向降解。

The CRL5-SPSB3 ubiquitin ligase targets nuclear cGAS for degradation.

机构信息

Global Health Institute, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland.

School of Medicine, Jiangnan University, Wuxi, China.

出版信息

Nature. 2024 Mar;627(8005):873-879. doi: 10.1038/s41586-024-07112-w. Epub 2024 Feb 28.

DOI:10.1038/s41586-024-07112-w
PMID:38418882
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10972748/
Abstract

Cyclic GMP-AMP synthase (cGAS) senses aberrant DNA during infection, cancer and inflammatory disease, and initiates potent innate immune responses through the synthesis of 2'3'-cyclic GMP-AMP (cGAMP). The indiscriminate activity of cGAS towards DNA demands tight regulatory mechanisms that are necessary to maintain cell and tissue homeostasis under normal conditions. Inside the cell nucleus, anchoring to nucleosomes and competition with chromatin architectural proteins jointly prohibit cGAS activation by genomic DNA. However, the fate of nuclear cGAS and its role in cell physiology remains unclear. Here we show that the ubiquitin proteasomal system (UPS) degrades nuclear cGAS in cycling cells. We identify SPSB3 as the cGAS-targeting substrate receptor that associates with the cullin-RING ubiquitin ligase 5 (CRL5) complex to ligate ubiquitin onto nuclear cGAS. A cryo-electron microscopy structure of nucleosome-bound cGAS in a complex with SPSB3 reveals a highly conserved Asn-Asn (NN) minimal degron motif at the C terminus of cGAS that directs SPSB3 recruitment, ubiquitylation and cGAS protein stability. Interference with SPSB3-regulated nuclear cGAS degradation primes cells for type I interferon signalling, conferring heightened protection against infection by DNA viruses. Our research defines protein degradation as a determinant of cGAS regulation in the nucleus and provides structural insights into an element of cGAS that is amenable to therapeutic exploitation.

摘要

环鸟苷酸-腺苷酸合酶 (cGAS) 在感染、癌症和炎症性疾病期间感知异常 DNA，并通过合成 2'3'-环鸟苷酸-腺苷酸 (cGAMP) 引发有效的先天免疫反应。cGAS 对 DNA 的无差别活性需要严格的调节机制，这对于维持正常条件下的细胞和组织稳态是必要的。在细胞核内，与核小体的锚定以及与染色质结构蛋白的竞争共同阻止基因组 DNA 激活 cGAS。然而，核 cGAS 的命运及其在细胞生理学中的作用仍然不清楚。在这里，我们表明泛素蛋白酶体系统 (UPS) 在有丝分裂细胞中降解核 cGAS。我们确定 SPSB3 是 cGAS 的靶向底物受体，它与 cullin-RING 泛素连接酶 5 (CRL5) 复合物结合，将泛素连接到核 cGAS 上。核小体结合的 cGAS 与 SPSB3 形成复合物的冷冻电子显微镜结构揭示了 cGAS 羧基末端的一个高度保守的 Asn-Asn (NN) 最小降解基序，该基序指导 SPSB3 的募集、泛素化和 cGAS 蛋白稳定性。干扰 SPSB3 调节的核 cGAS 降解使细胞对 I 型干扰素信号通路敏感，赋予对 DNA 病毒感染的更高保护。我们的研究将蛋白降解定义为核内 cGAS 调节的决定因素，并提供了对 cGAS 可治疗利用的一个元素的结构见解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b92/10972748/3819732a33e7/41586_2024_7112_Fig14_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b92/10972748/e6c577d81098/41586_2024_7112_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b92/10972748/b5ce6bcda63e/41586_2024_7112_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b92/10972748/95483b0fa23b/41586_2024_7112_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b92/10972748/22fa62297fb2/41586_2024_7112_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b92/10972748/195f03ba9d8d/41586_2024_7112_Fig5_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b92/10972748/0c0d0569ddc1/41586_2024_7112_Fig6_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b92/10972748/9288f6f2c197/41586_2024_7112_Fig7_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b92/10972748/370f1e18832b/41586_2024_7112_Fig8_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b92/10972748/dfa4ebbc3b8e/41586_2024_7112_Fig9_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b92/10972748/a218bfb59c07/41586_2024_7112_Fig10_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b92/10972748/4f4c4e585b86/41586_2024_7112_Fig11_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b92/10972748/843e910afc90/41586_2024_7112_Fig12_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b92/10972748/6a451196b6ee/41586_2024_7112_Fig13_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b92/10972748/3819732a33e7/41586_2024_7112_Fig14_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b92/10972748/e6c577d81098/41586_2024_7112_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b92/10972748/b5ce6bcda63e/41586_2024_7112_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b92/10972748/95483b0fa23b/41586_2024_7112_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b92/10972748/22fa62297fb2/41586_2024_7112_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b92/10972748/195f03ba9d8d/41586_2024_7112_Fig5_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b92/10972748/0c0d0569ddc1/41586_2024_7112_Fig6_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b92/10972748/9288f6f2c197/41586_2024_7112_Fig7_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b92/10972748/370f1e18832b/41586_2024_7112_Fig8_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b92/10972748/dfa4ebbc3b8e/41586_2024_7112_Fig9_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b92/10972748/a218bfb59c07/41586_2024_7112_Fig10_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b92/10972748/4f4c4e585b86/41586_2024_7112_Fig11_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b92/10972748/843e910afc90/41586_2024_7112_Fig12_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b92/10972748/6a451196b6ee/41586_2024_7112_Fig13_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b92/10972748/3819732a33e7/41586_2024_7112_Fig14_ESM.jpg

相似文献

1
The CRL5-SPSB3 ubiquitin ligase targets nuclear cGAS for degradation.CRL5-SPSB3 泛素连接酶将核 cGAS 靶向降解。
Nature. 2024 Mar;627(8005):873-879. doi: 10.1038/s41586-024-07112-w. Epub 2024 Feb 28.
2
Keeping cGAS in check: SPSB3 promotes nuclear cGAS degradation for maintaining immune homeostasis.保持 cGAS 的平衡：SPSB3 促进核 cGAS 降解，以维持免疫稳态。
Mol Cell. 2024 May 2;84(9):1635-1636. doi: 10.1016/j.molcel.2024.04.003.
3
Structural mechanism of cGAS inhibition by the nucleosome.核小体抑制 cGAS 的结构机制。
Nature. 2020 Nov;587(7835):668-672. doi: 10.1038/s41586-020-2750-6. Epub 2020 Sep 10.
4
Structural basis for sequestration and autoinhibition of cGAS by chromatin.染色质对 cGAS 的隔离和自动抑制的结构基础。
Nature. 2020 Nov;587(7835):678-682. doi: 10.1038/s41586-020-2748-0. Epub 2020 Sep 10.
5
The molecular basis of tight nuclear tethering and inactivation of cGAS.紧密核束缚和 cGAS 失活的分子基础。
Nature. 2020 Nov;587(7835):673-677. doi: 10.1038/s41586-020-2749-z. Epub 2020 Sep 10.
6
Structural basis for nucleosome-mediated inhibition of cGAS activity.核小体介导的 cGAS 活性抑制的结构基础。
Cell Res. 2020 Dec;30(12):1088-1097. doi: 10.1038/s41422-020-00422-4. Epub 2020 Oct 13.
7
MARCH8 attenuates cGAS-mediated innate immune responses through ubiquitylation.MARCH8 通过泛素化来衰减 cGAS 介导的先天免疫反应。
Sci Signal. 2022 May 3;15(732):eabk3067. doi: 10.1126/scisignal.abk3067.
8
Sumoylation Promotes the Stability of the DNA Sensor cGAS and the Adaptor STING to Regulate the Kinetics of Response to DNA Virus.SUMOylation 促进 DNA 传感器 cGAS 和衔接蛋白 STING 的稳定性，以调节对 DNA 病毒的反应动力学。
Immunity. 2016 Sep 20;45(3):555-569. doi: 10.1016/j.immuni.2016.08.014. Epub 2016 Sep 13.
9
Tegument protein UL21 of alpha-herpesvirus inhibits the innate immunity by triggering CGAS degradation through TOLLIP-mediated selective autophagy.α疱疹病毒的被膜蛋白 UL21 通过 TOLLIP 介导的选择性自噬触发 CGAS 降解来抑制先天免疫。
Autophagy. 2023 May;19(5):1512-1532. doi: 10.1080/15548627.2022.2139921. Epub 2022 Nov 7.
10
Structural basis of nucleosome-dependent cGAS inhibition.核小体依赖性 cGAS 抑制的结构基础。
Science. 2020 Oct 23;370(6515):450-454. doi: 10.1126/science.abd0609. Epub 2020 Sep 10.

引用本文的文献

1
The cGAS-STING pathway: a dual regulator of immune response in cancer and therapeutic implications.环鸟苷酸-腺苷酸合成酶-干扰素基因刺激蛋白（cGAS-STING）信号通路：癌症免疫反应的双重调节因子及其治疗意义
J Transl Med. 2025 Jul 10;23(1):766. doi: 10.1186/s12967-025-06843-2.
2
TXNIP promotes viral replication by disrupting MAVS-mediated antiviral signaling and serves as a therapeutic target for antiviral therapy.硫氧还蛋白相互作用蛋白（TXNIP）通过破坏线粒体抗病毒信号蛋白（MAVS）介导的抗病毒信号传导来促进病毒复制，并作为抗病毒治疗的一个治疗靶点。
Redox Biol. 2025 Jul 5;85:103756. doi: 10.1016/j.redox.2025.103756.
3
KDM4B enhances immune surveillance via demethylating cGAS.

本文引用的文献

1
Clathrin-associated AP-1 controls termination of STING signalling.网格蛋白相关衔接蛋白-1 控制 STING 信号的终止。
Nature. 2022 Oct;610(7933):761-767. doi: 10.1038/s41586-022-05354-0. Epub 2022 Oct 19.
2
CUL5-ARIH2 E3-E3 ubiquitin ligase structure reveals cullin-specific NEDD8 activation.CUL5-ARIH2 E3-E3 泛素连接酶结构揭示了连接酶的特异性 NEDD8 激活。
Nat Chem Biol. 2021 Oct;17(10):1075-1083. doi: 10.1038/s41589-021-00858-8. Epub 2021 Sep 13.
3
The cGAS-STING pathway as a therapeutic target in inflammatory diseases.
KDM4B通过使环鸟苷酸-腺苷酸合成酶（cGAS）去甲基化来增强免疫监视。
Cell Death Dis. 2025 Jul 1;16(1):478. doi: 10.1038/s41419-025-07792-w.
4
cGAS, an innate dsDNA sensor with multifaceted functions.环鸟苷酸-腺苷酸合成酶（cGAS），一种具有多种功能的天然双链DNA传感器。
Cell Insight. 2025 Apr 17;4(3):100249. doi: 10.1016/j.cellin.2025.100249. eCollection 2025 Jun.
5
Interferon-induced protein ISG15 in the central nervous system, quo vadis?中枢神经系统中干扰素诱导蛋白ISG15，何去何从？
FEBS Lett. 2025 May 12. doi: 10.1002/1873-3468.70063.
6
is not essential for spermatogenesis and male fertility in mice.对小鼠的精子发生和雄性生育能力并非必不可少。
Am J Transl Res. 2025 Mar 15;17(3):1814-1823. doi: 10.62347/TVPV4242. eCollection 2025.
7
Induction of translation-suppressive G3BP1 stress granules and interferon-signaling cGAS condensates by transfected plasmid DNA.转染的质粒DNA诱导翻译抑制性G3BP1应激颗粒和干扰素信号cGAS凝聚物的形成。
Hlife. 2025 Jan;3(1):21-37. doi: 10.1016/j.hlife.2024.11.005. Epub 2024 Dec 24.
8
PCK1 inhibits cGAS-STING activation by consumption of GTP to promote tumor immune evasion.磷酸烯醇式丙酮酸羧激酶1（PCK1）通过消耗鸟苷三磷酸（GTP）抑制环磷酸鸟苷-腺苷酸合成酶（cGAS）-干扰素基因刺激蛋白（STING）激活，从而促进肿瘤免疫逃逸。
J Exp Med. 2025 May 5;222(5). doi: 10.1084/jem.20240902. Epub 2025 Mar 6.
9
The role of cGAS-STING pathway ubiquitination in innate immunity and multiple diseases.环鸟苷酸-腺苷酸合成酶-干扰素基因刺激蛋白（cGAS-STING）通路泛素化在固有免疫及多种疾病中的作用
Front Immunol. 2025 Feb 14;16:1522200. doi: 10.3389/fimmu.2025.1522200. eCollection 2025.
10
Targeting the PRMT1-cGAS-STING signaling pathway to enhance the anti-tumor therapeutic efficacy.靶向PRMT1-cGAS-STING信号通路以提高抗肿瘤治疗效果。
J Cancer Biol. 2024;5(2):44-60. doi: 10.46439/cancerbiology.5.064.
cGAS-STING 通路作为炎症性疾病的治疗靶点。
Nat Rev Immunol. 2021 Sep;21(9):548-569. doi: 10.1038/s41577-021-00524-z. Epub 2021 Apr 8.
4
Ubiquitin ligation to F-box protein targets by SCF-RBR E3-E3 super-assembly.SCF-RBR E3-E3 超级组装对 F-box 蛋白靶标的泛素连接。
Nature. 2021 Feb;590(7847):671-676. doi: 10.1038/s41586-021-03197-9. Epub 2021 Feb 3.
5
A Nuclear Export Signal Is Required for cGAS to Sense Cytosolic DNA.一种核输出信号对于 cGAS 识别细胞质 DNA 是必需的。
Cell Rep. 2021 Jan 5;34(1):108586. doi: 10.1016/j.celrep.2020.108586.
6
Structural mechanism of cGAS inhibition by the nucleosome.核小体抑制 cGAS 的结构机制。
Nature. 2020 Nov;587(7835):668-672. doi: 10.1038/s41586-020-2750-6. Epub 2020 Sep 10.
7
The molecular basis of tight nuclear tethering and inactivation of cGAS.紧密核束缚和 cGAS 失活的分子基础。
Nature. 2020 Nov;587(7835):673-677. doi: 10.1038/s41586-020-2749-z. Epub 2020 Sep 10.
8
Structural basis for sequestration and autoinhibition of cGAS by chromatin.染色质对 cGAS 的隔离和自动抑制的结构基础。
Nature. 2020 Nov;587(7835):678-682. doi: 10.1038/s41586-020-2748-0. Epub 2020 Sep 10.
9
BAF restricts cGAS on nuclear DNA to prevent innate immune activation.BAF通过限制核DNA上的cGAS来防止先天性免疫激活。
Science. 2020 Aug 14;369(6505):823-828. doi: 10.1126/science.aaw6421.
10
Molecular mechanisms and cellular functions of cGAS-STING signalling.cGAS-STING 信号转导的分子机制和细胞功能。
Nat Rev Mol Cell Biol. 2020 Sep;21(9):501-521. doi: 10.1038/s41580-020-0244-x. Epub 2020 May 18.